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Neuromuscular rehabilitation and electrodiagnosis. 2. Peripheral neuropathy
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Neuromuscular Rehabilitation and Electrodiagnosis. 2. Peripheral Neuropathy Lyn D. Weiss, MD, Jay M. Weiss, MD, Jeffery S. Johns, MD, Jeffrey A. Strommen, MD, Chong-Tae Kim, MD, PhD, Faren H. Williams, MD, MS, Ira G. Rashbaum, MD ABSTRACT. Weiss LD, Weiss JM, Johns JS, Strommen JA, Kim C-T, Williams FH, Rashbaum IG. Neuromuscular rehabilitation and electrodiagnosis. 2. Peripheral neuropathy. Arch Phys Med Rehabil 2005;86(3 Suppl 1):S11-7. This self-directed learning module highlights peripheral neuropathies. It is part of the chapter on neuromuscular rehabilitation and electrodiagnosis in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on diagnostic criteria and classifications of peripheral neuropathy, including diabetic, alcoholic, carcinomatous, human immunodeficiency virus–associated, and critical illness polyneuropathies. Treatment options are reviewed. The causes for difficult to obtain nerve conduction studies are highlighted. Overall Article Objective: To summarize the diagnosis, classification, and treatment of peripheral neuropathies. Key Words: Alcoholic neuropathy; Carcinoma; Critical illness; Electrodiagnosis; HIV; Peripheral neuropathies; Rehabilitation; Treatment outcome. © 2005 by the American Academy of Physical Medicine and Rehabilitation 2.1
Clinical Activity: To clarify electrodiagnostic medicine’s role in establishing the cause of bilateral hand and foot numbness with pain in a 64-year-old woman with diabetes, breast cancer, and alcoholism.
The electromyographer has a responsibility to provide the referring physician with as much physiologic information as possible about both diagnosis and prognosis. In a case of possible peripheral neuropathy (PN), the history must include elements of duration, location, and intensity of symptoms, information about any relatives with similar disorders to assess for a hereditary neuropathy, previous cancers and their treatments, if any, and other medical problems that can be associated with PN. These include diabetes, hypothyroidism, human immunodeficiency virus (HIV), side effects from medications, alcoholism, uremia, toxic exposures, connective tissue disorders, infectious processes, and nutritional deficiencies. The
From the Department of Physical Medicine and Rehabilitation, Nassau University Medical Center, East Meadow, NY (LD Weiss); Long Island PMR, Levittown, NY (JM Weiss); Department of Physical Medicine and Rehabilitation, Charlotte Institute of Rehabilitation, Charlotte, NC (Johns); Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN (Strommen); Division of Child Development and Rehabilitation, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA (Kim); Section of Physical Medicine and Rehabilitation, Philadelphia Veterans Administration Medical Center and University of Pennsylvania, Philadelphia, PA (Williams); and Department of Rehabilitation Medicine, New York University Medical Center, New York, NY (Rashbaum). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Lyn D. Weiss, MD, Nassau University Med Ctr, Dept of PM&R, 2201 Hempstead Tpke, East Meadow, NY 11554, e-mail: [email protected]. 0003-9993/05/8603S-9586$30.00/0 doi:10.1016/j.apmr.2004.12.004
physical examination may help differentiate a PN (generally distal) from a localized peripheral nerve entrapment. The diagnosis of PN typically requires an electrodiagnostic examination of at least 3 limbs, including both sensory and motor studies, as well as needle testing. The temperature of the limbs should be maintained at 32°C in the upper extremities and 30°C in the lower extremities. Decreased temperatures can lead to spuriously false results on nerve conduction studies (NCSs), including increased amplitudes, prolonged latencies, and slowed nerve conduction velocities (NCVs). Once the diagnosis of PN is clear, the electromyographer should clarify its type in order to determine the cause and severity. PN can be grouped into primarily axonal, primarily demyelinating, or mixed. It can further be divided into those neuropathies that affect primarily motor fibers, sensory fibers, or both. It can be classified as segmental (affecting only certain areas of the nerve) or uniform (affecting the entire length of the nerve). The referring physician will also need to know the severity of the PN. Furthermore, a thorough electrodiagnostic study may reveal a superimposed peripheral nerve entrapment, because patients with PN are frequently predisposed to compression neuropathies. Needle electromyography is an important component of the evaluation. In axonal neuropathies, the chronicity of the lesion can be estimated based on needle findings. Large amplitude, long duration, polyphasic motor units are consistent with a more chronic (⬎6-mo) process. Needle studies are also indicated to determine if other conditions are superimposed on the neuropathy. For example, needle abnormalities limited to a peripheral nerve distribution may point to a superimposed mononeuropathy. Needle abnormalities only in the paraspinal muscles may suggest a polyradiculopathy. In this patient, several types of neuropathy are suggested by the presentation. The history of diabetes would suggest diabetic neuropathy (DN). DN represents a spectrum of different syndromes, ranging from subclinical to clinical, depending on the nerve fibers involved.1 DN will affect both motor and sensory fibers, and have both demyelinating and axonal components. This will frequently present with numbness in a stocking and glove distribution and with distal muscle wasting. Alcoholic neuropathy, primarily an axonal sensory and motor neuropathy, has an unclear etiology. It is most likely caused either by a direct toxic effect of the alcohol or by a nutritional deficiency of the vitamin B group, giving symptoms in a stocking and glove distribution. Carcinomatous neuropathy, an axonal sensory neuropathy with a stocking and glove presentation, is characterized by decreased amplitude of the sensory nerve action potential (SNAP) with generally normal or near normal latencies and unaffected motor studies. Because there is usually sparing of the motor axons, the needle electromyography will usually appear normal. Neuropathy associated with chemotherapeutic agents has a variable presentation depending on the type of agent. Cisplatin toxicity typically presents with a sensory axonal neuropathy. Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
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Vincristine neuropathy typically presents with an axonal neuropathy that involves motor nerves more than sensory nerves.2 Other possible causes of PN in this patient include trauma associated with surgery (especially positioning), nerve damage during axillary node dissection, radiation plexopathy, or a paraneoplastic syndrome. Radiation plexopathy and trauma associated with surgery would not give a bilateral stocking and glove distribution, as was presented here, but can be a complicating factor in the diagnosis. Radiation plexopathy will classically show myokymic discharges (a sound described as marching soldiers) on needle electromyography. Paraneoplastic syndrome neuropathy typically demonstrates axonal loss, affecting motor more than sensory nerves. While the nerve study and needle electromyography are both important, in PN the NCSs take on greater importance. NCSs can distinguish between demyelinating and axonal lesions, and sensory fibers are not assessed by needle electromyography. The most important part of the electrodiagnostic consult is to place the data into the appropriate clinical context. The findings should note the primary electrophysiologic lesion. For example, if the patient has generally mildly increased distal latencies and mild slowing, but SNAP amplitudes in the arms and legs are unobtainable or severely decreased, then the primary lesion is an axonal sensory neuropathy. Theoretically, the latency and NCV should not be affected in an axonal neuropathy. However, because some of the fastest fibers may be affected in an axonal lesion, a mild reduction in NCV may be noted. An NCV reduction of 70% to 80% or more, compared to the contralateral side or the distal segment, would be considered significant. There may be a concomitant demyelinating motor neuropathy that complicates the picture. These findings must be discussed in the clinical context. Table 1 delineates the possible causes of neuropathy as revealed by the electrodiagnostic findings.3 2.2
Clinical Activity: To delineate treatment options in this patient.
Once PN has been diagnosed, treatment options should be initiated. Although a plethora of treatments exists, none is a panacea. Usually, trials of different medications titrated to effective dosage must be attempted before the most adequate treatment is instituted. The first objective is to treat or remove the underlying cause for the PN. Electrodiagnosis can help categorize the neuropathy type (ie, axonal or demyelinating, sensory or motor, uniform or segmental). Often, other tests are required to confirm the diagnosis. If axonal neuropathy was evident, and the patient had an extensive history of alcohol use, blood samples should be obtained to assess for nutritional deficiencies. Cessation of alcohol, vitamin supplementation (specifically B vitamins and magnesium), and dietary changes may decrease the symptoms of neuropathy. The most important preventive measure for type 1 DN appears to be adequate glucose control.4 Medications for PN generally fall into the following categories: tricyclic agents, anticonvulsants, antiarrhythmics, topical solutions, clonidine, and opioids.5 Nonpharmaceutical treatments should be considered as adjuvants to medication, especially in patients who are unable to tolerate the full dosage because of contraindications or side effects. These include transcutaneous electric nerve stimulation, heat, ice, biofeedback, meditation, acupuncture, and hypnosis. Titrated doses of several medications may be tried before an adequate response is obtained. First-line choices often depend on the characteristics of neuropathic pain.6 Anticonvulsants are usually the first medication prescribed for trigeminal neuralgia. Continuous burning dysesthesias, such as those seen in DN, Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
usually respond to tricyclic agents. Therapy should be oriented toward the treatment of pain, based on the proposed mechanism for pain generation. The tricyclic agents are a good first-line medication for patients with neuropathy. They have the added benefit of a positive effect on mood, although patients are typically started on a dose that would be considered subtherapeutic to treat depression. The mechanism of action is not known. Amitriptyline, nortriptyline, imipramine, and desipramine have been successfully used. Typical starting dose for amitriptyline is 25mg at bedtime. The dose must be gradually titrated for maximum effect before switching to another medication. The dosage can be increased by 10 to 25mg every 3 to 7 days up to a total of 150mg. Usually 3 to 4 weeks of medication is required before an effect is noted. Anticonvulsants have also been used with success in treating neuropathies. Phenytoin, carbamazepine, and gabapentin have been most frequently used. Gabapentin has gained increasing popularity because of its low side-effect profile. Patients can be started at 300mg at night, and quickly titrated to up to 1200mg (or occasionally greater) 3 times a day. Gabapentin may be effective in neuropathic pain because of its effect on calcium channels. The rationale for using anticonvulsants is based on the similarities between the pathophysiologic and biochemical mechanisms in both epilepsy and neuropathy. Apparently, primary afferent fibers are susceptible to the effects of sodium and calcium channel blockade. Blocking these channels would theoretically reduce spontaneous and evoked neural discharges.7 The efficacy of some of the newer anticonvulsant medications, including lamotrigine and zonisamide, is still being evaluated.7-9 Antiarrhythmics such as intravenous lidocaine and oral mexiletine, which block sodium channels, have been used in neuropathic disorders. These medications are not as frequently prescribed because of their high side-effect profile. Intravenous lidocaine must be administered in a recovery room or other monitored setting because of the risk of seizures or cardiac arrhythmias. Any patient with a cardiac history or abnormal electrocardiogram should have cardiology clearance before starting mexiletine. Recently, the use of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists has been used to treat patients with painful DN. The mechanism of action is antagonism of voltage-dependent calcium channels and NMDA receptor operated channels. Whereas dextromethorphan was noted to be effective in a dose-related fashion in selected DN patients, it was not effective in postherpetic neuralgia, suggesting a difference in the pain mechanism.10 Topical preparations, such as lidocaine, capsaicin cream, or clonidine, have the advantage of decreased systemic effects. Capsaicin is thought to decrease pain by depleting substance P.5 However, it produces intense burning and must be applied 3 to 4 times per day. The efficacy of these topical agents has been questioned.5 Use of opioids in neuropathic pain remains controversial. They may be more efficacious if used in combination with other agents. The starting dosage should be low and titrated to maximum effectiveness. Recent studies11 with controlled-release oxycodone showed it to be effective in the treatment of painful DN. Choosing the most appropriate medication and dosage requires patience on the part of both the clinician and the patient. The goal of therapy is to provide optimal analgesia with a minimum of side effects.
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PERIPHERAL NEUROPATHY, Weiss Table 1: Classification and Electrodiagnostic Findings of PN
EMG Finding CMAP amplitude Motor latency Motor conduction velocity Dispersion of CMAP SNAP amplitude SNAP conduction velocity Needle EMG: Would fibs and PSWs likely be noted? Common diseases
Uniform Demyelinating Mixed Sensorimotor PN Normal
Segmental Demyelinating Motor ⬎ Sensory PN
Axon Loss Motor ⬎ Sensory PN
Sensory Axon Loss Neuropathy
Axon Loss Mixed Sensorimotor PN
Mixed Axonal Loss and Demyelinating Sensorimotor PN
Decreased
Normal
Decreased
Decreased
Increased Decreased
Decreased secondary to dispersion Increased Decreased
Normal Normal
Normal Normal
Normal Normal
Increased Decreased
No
Yes
No
No
No
Yes (mild)
Normal
Normal
Decreased (usually)
Decreased
Decreased
Decreased
Decreased
Decreased (somewhat)
Normal
Normal
Normal
Decreased
No (normal)
No (normal)
Yes
No (normal)
Yes
Yes
1. Hereditary motor sensory neuropathy type 1, 3, 6 (distal weakness with little atrophy) 2. Metachromatic leukodystrophy 3. Krabbe’s leukodystrophy 4. Adrenomyeloneuropathy 5. Congenital hypomyelinating neuropathy 6. Tangier disease 7. Cockayne’s syndrome 8. Cerebrotendinous xanthomatosis
1. AIDP: GuillainBarré syndrome (ascending proximal weakness) 2. CIDP (weakness of asymmetric low extremities) 3. Recurrent inflammatory PN (proximal weakness) 4. Osteosclerotic myeloma 5. Hypothyroidism (sensory ⬎ motor) (distal symmetric weakness) 6. Leprosy 7. Acute arsenic PN 8. Pharmaceuticals: amiodarone, perhexiline, high-dose Ara-C 9. Carcinoma 10. AIDS
1. Remote-effect motor neuropathy associated with carcinoma (distal weakness) 2. Porphyria 3. Axonal GuillainBarré syndrome 4. Hereditary motor sensory neuropathy types 2 and 5 5. Lead neuropathy 6. Dapsone neuropathy 7. Vincristine neuropathy 8. Remote-effect motor neuropathy associated with lymphoma 9. Hypoglycemia hyperinsulinemia
1. Carcinomatous (neuropathic pain in distal extremities) 2. Hereditary sensory neuropathy types 1– 4 3. Friedreich’s ataxia 4. Spinocerebellar degeneration 5. Abetalipoproteinema (Bassen-Kornzweig disease) 6. Primary biliary cirrhosis 7. Acute sensory neuronopathy cisplatin toxicity 8. Lymphomatous sensory neuronopathy 9. Chronic idiopathic ataxic neuropathy 10. Sjögren’s syndrome 11. Fisher-variant Guillain-Barré syndrome 12. Paraproteinemias 13. Pyridoxine toxicity
1. Alcoholic PN (distal symmetric weakness) 2. Vitamin (thiamine, B12, folate) deficiency (distal symmetric weakness) 3. Gouty neuropathy 4. Metal neuropathy (eg, mercury, thallium, gold) 5. Sarcoidosis 6. Connective tissue diseases (eg, rheumatoid arthritis, SLE) 7. Gastrectomy, gastric restriction surgery for obesity 8. Chronic liver disease 9. Neuropathy of chronic illness (eg, hypothyroidism, myotonic dystrophy, AIDS, Lyme disease) 10. Toxic neuropathy (acrylamide, carbon disulfide, carbon monoxide)
1. Diabetic PN (distal symmetric weakness) 2. Uremia (distal symmetric weakness)
Reprinted with permission from Weiss et al.3 Abbreviations: AIDP, acute inflammatory demyelinating polyradiculoneuropathy; AIDS, acquired immunodeficiency syndrome; CIDP, chronic inflammatory demyelinating polyneuropathy; CMAP, compound motor action potential; EMG, electromyography; fibs, fibrillation potentials; PSWs, positive sharp waves; SLE, systemic lupus erythematosus.
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Clinical Activity: To comment on the investigation and care of a 57-year-old man who is seropositive for HIV and presenting with distal weakness and sensory disturbances.
Neuromuscular disorders, including primary myopathies and PNs, are the most frequent neurologic complications of HIV and acquired immune deficiency syndrome (AIDS).12 The estimated prevalence of some form of PN in patients with HIV is 15% to 45%, based on clinical findings, but may be higher if electrophysiologic or nerve biopsy findings are considered.13,14
Although this patient has symptoms consistent with a PN, myopathies must be considered. HIV-associated myopathies occur in 3 primary forms: inflammatory myopathy, zidovudine myopathy, and pyomyositis.15 The inflammatory form can occur at any point in the course of HIV infection and results in proximal weakness and, less commonly, myalgias. Creatine kinase (CK) may be elevated, and electromyography findings include myopathic motor units and abnormal spontaneous activity typical of an inflammatory myopathy. Muscle biopsy findings include fiber size variability, fiber degeneration, and endomysial infiltrates along Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
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with cytoplasmic bodies and nemaline rod bodies.15 The exact pathogenesis of this inflammatory myopathy is not known, but HIV does not appear to infect muscle fibers directly, and triggers cell-mediated muscle injury by expressing major histocompatibility complex 1.12 Treatment is reserved only for significant weakness that impairs function and includes cautious use of corticosteroids. Zidovudine myopathy is clinically difficult to distinguish from the inflammatory form. It presents with an insidious onset of proximal weakness and myalgia with a normal or elevated CK. Patients typically have taken zidovudine for at least 6 months, and muscle biopsy suggests mitochondrial dysfunction, with varying degrees of inflammation.15 Pyomyositis is a focal, suppurative bacterial muscle infection presenting with fever, local muscle pain, and swelling evolving over several weeks. White blood cell count and CK are usually normal, and the diagnosis can be made using computed tomography, magnetic resonance imaging (MRI), or ultrasound. The causative organism is typically Staphylococcus aureus, or, less commonly, Salmonella or other gram-negative bacilli. Treatment includes antibiotics and possible surgical drainage.15 HIV-associated peripheral nerve disorders have been classified into at least 5 main categories: distal symmetric polyneuropathy, inflammatory demyelinating polyneuropathy, mononeuropathy multiplex, progressive polyradiculopathy, and autonomic neuropathy.12,16 Others include diffuse infiltrative lymphocytosis syndrome and herpes zoster radiculitis.12,14 Distal symmetric PN is the most common form of peripheral nerve disorder in patients with HIV.13,16 It affects 25% to 38% of patients with HIV and up to 48% to 52% of patients with AIDS.12,13,17 There is a correlation with lower hemoglobin, lower functional status, and, possibly, advanced age.12,13,17 Symptoms include ascending distal numbness, paresthesias, and painful dysesthesias usually beginning in the toes.12,13,16 Clinical signs include reduced sensation to vibration, pain, and temperature in a stocking distribution, mildly reduced foot intrinsic strength with mild wasting, and absent or depressed ankle reflexes.12,13,16 Hyperactive knee reflexes may indicate central nervous system (CNS) dysfunction, such as myelopathy.12 Position sense loss associated with distal symmetric PN has a reported occurrence of 19%.13 Advanced cases may also involve the upper extremities in a distal and symmetrical pattern.12 Hand intrinsic strength is typically preserved until late in the disease course.16 Nerve biopsies reveal predominately axonal loss with Wallerian-like degeneration of myelinated and unmyelinated fibers.18 Possible causes include cytomegalovirus (CMV), inflammatory processes, nutritional deficiencies, and diabetes; however, most patients have no identifiable cause.18 A subset of patients with distal symmetric PN may also have necrotizing vasculitis.14 Distal symmetric PN may also be mimicked by toxic neuropathies from medications such as zalcitabine, didanosine, and stavudine.17 Diagnosis of distal symmetric PN is typically clinical, and alternative causes of neuropathy should be ruled out. Electrodiagnostic findings are consistent with a distal axonal sensory and motor polyneuropathy and include reduced sensory and motor nerve amplitudes and, to a lesser extent, the NCV, prolonged late responses, and neurogenic changes in the distal leg muscles on needle electromyography.12,16 Treatment of distal symmetric PN is primarily symptomatic, but investigational trials are ongoing using recombinant human nerve growth factor and prouridine.12 The incidence of HIV-related inflammatory demyelinating PN is approximately 4%,13 and occurs in an acute or a chronic form. The acute form often occurs at the time of seroconversion to HIV positivity.12 Clinical features, electrodiagnostic Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
findings, and pathogenesis of the acute form are similar for people with or without HIV infection. CMV may cause inflammatory demyelinating PN by directly infecting peripheral nerves, but nerve biopsies typically demonstrate primarily segmental demyelination with variable degrees of axonal loss.12,16 Cerebrospinal fluid (CSF) shows elevated protein and lymphocytic pleocytosis, which differs from the acellular CSF of typical acute inflammatory demyelinating PN.12,14 Given the similarities in clinical presentation and diagnostic findings, consider HIV testing in any patient with acute or chronic inflammatory demyelinating PN with HIV risk factors or suspicious laboratory results.14 Treatment includes corticosteroids, plasmapheresis, and high-dose intravenous immunoglobulin.12,15 HIV-related mononeuropathy multiplex occurs in 2 forms, one occurring in immunocompetent patients and probably immune mediated, self-limiting, and showing a good response to corticosteroids, and the other being more progressive and extensive and occurring in immunocompromised patients (CD4 ⬍50).12,14,15 One study13 found the overall incidence of mononeuropathy multiplex to be 11% in HIV-positive patients. Clinical presentation includes reduced sensation or paresthesias in a pattern suggesting multiple peripheral nerves or cutaneous sensory nerves rather than a nerve root or symmetric disorder of all distal nerves. Marked asymmetry is typical, and strength and reflexes are normal in nonaffected peripheral nerve distributions.16 There are 3 primary histopathologies: most commonly, a combination of perivascular inflammation and axonal loss; occasionally, a combination of demyelination and axonal loss with multinucleated inflammatory cells; and, least commonly, a vasculitic lesion that creates a pattern of necrotizing vasculitis.16 Electromyography findings of mononeuropathy multiplex include multifocal and asymmetric pathology of cranial, sensory, and motor nerves with axonal or demyelinating pathology.12 Mononeuropathy multiplex commonly occurs concurrently with distal symmetric PN.16 Sural nerve biopsy may reveal evidence of primary CMV infection, and CSF studies should include a CMV assay.12 Treatment considerations for CMV infection may include ganciclovir, foscarnet, and cidofovir alone or in combination.12 The incidence of patients with HIV-related progressive polyradiculopathy is approximately 1%,13 and it occurs mainly in late stages of the disease.12,16 It is typically associated with opportunistic infections, typically CMV, and more rarely, syphilis, mycobacterial infections, toxoplasmosis, and leptomeningeal lymphomatosis.14,15 Clinical presentation includes radiating pain and paresthesias in the cauda equina distribution, rapidly progressive flaccid paraparesis, lower-extremity areflexia, mild sensory loss including the perineum, and neurogenic bowel and bladder.12,14-16 In a patient with a thoracic or cervical sensory level lesion, a concurrent myelopathy should be considered. Nerve root biopsies typically reveal CMV inclusions as well as significant degrees of inflammatory infiltrates associated with varying degrees of axonal loss.16 Electromyography findings are variable and include low-amplitude compound muscle action potentials (CMAPs), prolonged or absent F waves, reduced or absent SNAPs, and diffuse abnormal spontaneous activity on needle electromyography.16 CSF reveals marked polymorphonuclear pleocytosis, elevated protein, and low to normal glucose with cultures or assays positive for CMV.12,15 MRI with gadolinium may demonstrate enhancement of cauda equina nerve roots.14 Treatment is targeted toward CMV as discussed for mononeuropathy multiplex above.12 This CMV treatment may preserve neurologic function; however, the patient’s long-term prognosis is poor.14
PERIPHERAL NEUROPATHY, Weiss
The incidence of HIV-related autonomic neuropathy is approximately 1%.13 Findings may include resting tachycardia, orthostatic hypotension, syncope, impotence, urinary dysfunction, diarrhea, and anhidrosis. The exact pathophysiology is unknown but is thought to be caused by multiple factors. The diagnosis is clinical, and treatment is supportive and symptombased.12 Herpes zoster radiculitis occurs in about 10% of patients with HIV and may present early in the disease, at the time of seroconversion, or during asymptomatic periods. Ataxia from polyganglionopathy may develop.14 Symptoms and treatment are similar to HIV-seronegative patients. 2.4
Clinical Activity: To list the potential causes of difficulty obtaining NCSs in this patient.
There may be several technical reasons for obtaining an abnormal waveform, assuming that there are no physiologic reasons. One of the most common reasons is inappropriate gain and/or sweep setting. Patients with PN may have prolonged latencies, low amplitudes, and slowed NCVs. If the gain is set too low, the waveform amplitude and takeoff may not be readily observed. Increasing the gain will help identify the waveform and its parameters.19 If the sweep speed is too slow, the takeoff may be to the right of the screen. Increasing the sweep speed will help identify waveforms that have very prolonged latencies. In instances of unobtainable CMAPs or SNAPs, the initial assumption should be that this is caused by technical factors, including failure to stimulate the nerve or a failure to record the evoked response properly. If nerve stimulation elicits a visible contraction in the appropriate muscle, the stimulator is functioning and the nerve is being depolarized, so one should increase the intensity and/or the pulse width. If a shock is not felt, the problem may be a lack of stimulus. Check wires and settings or replace the stimulator. If the stimulator is functioning, check proper positioning and/or stimulate a more superficial or consistent site. For example, a CMAP that is obtainable proximally and not distally suggests poor localization of the stimulator or perhaps an anomalous innervation, not a neuropathic process. If there is a problem with the waveform recording, check that the preamplifier is not turned off. Check the wires, and lightly touch one of the electrodes. If the speaker is on, you should hear noise from the electrode (especially with a sensory test set-up). If there is no noise, there probably is a technical problem. Recheck settings, including which amplifier/preamplifier (if more than 1 channel) is on. A study should be considered unobtainable only after methodically ruling out a problem stimulating a nerve or a problem with recording. At this point, a different nerve should be stimulated to check for recording. For example, in motor nerves, if a CMAP is unobtainable from the median nerve at the abductor pollicis brevis muscle, stimulate the ulnar nerve with the same pickup. The ulnar innervated thenar muscles will give a CMAP verifying that the stimulator, electrodes, and preamplifier and circuitry are working. Similarly, sensory studies can be performed on digits with dual innervation (digit 1 for radial and median nerves, digit 4 for median and ulnar nerves). Another common problem, especially in PN patients, is distal muscle wasting. If the active electrode is over an atrophied muscle, the CMAP amplitude will be low, giving the false impression that there is axonal injury. One should test a more proximal muscle innervated by the same nerve.
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For example, if the extensor digitorum brevis (EDB) is atrophied, move the active electrode to the tibialis anterior. If a normal CMAP is obtained, the problem may be an axonal injury to the peroneal nerve distal to the branch to the tibialis anterior muscle, or it may be caused by an atrophied EDB muscle, either from a PN or from non-neuropathic factors such as tight shoes. Temperature can also change the latency, NCV, and amplitude of waveforms. PN patients frequently have concurrent vascular disorders, occasionally associated with cold extremities. Warming the extremity to 30°C in the lower limbs and to 32°C in the upper limbs could decrease the amplitude and distal latency, but increase the NCV. In general, latency is prolonged 0.2ms per degree Celsius, and conduction velocity decreases 1.8 to 2.4m/s per degree Celsius.20 Any outside electric interference can distort or obliterate a waveform. Checking all wires, ensuring the ground is in place (and located between the recording and stimulating electrodes), ensuring all contacts are complete, and trying to decrease outside interference (eg, lights, radios) can help. Because most electric interference is 60 cycles, many electromyographs have a 60-cycle notch filter that selectively filters out all 60-cycle waves. Sometimes, using a shorter wire, especially with SNAPs, can decrease interference. Ensuring that filter settings and impedance are appropriate is essential. Cleansing the skin with alcohol or an abrading agent may help to decrease impedance. Another common source of error is not stimulating directly over the nerve. If this occurs, the amplitude will appear spuriously lower. Furthermore, if there is appreciable adipose tissue, connective tissue, or fluid between the nerve and the stimulator, the amplitude will appear decreased because of submaximal stimulation. Sometimes, increasing the stimulation or the pulse width may help this situation. However, if the stimulation and/or pulse width are too high, a nearby nerve may be mistakenly stimulated, leading to volume conduction. Excessive stimulation can cause depolarization further away from the cathode, the equivalent of stimulating further down the nerve, and giving a falsely increased NCV. With excessive adipose tissue, needle testing can be misleading. If the active electrode is not over the motor point of the nerve, the amplitude may appear decreased, and the CMAP may have an initial positive deflection. Initial positive deflections can also be seen in cases of anomalous innervation, the most commonly being the Martin-Gruber anastomosis and the accessory peroneal nerve. Age, weight, and height can also affect the expected waveform morphology. NCSs are often performed on older patients to assess for PN. NCVs can decrease by 1 to 2m/s per decade of life.21 Amplitudes also can be expected to decrease with increasing age. Patients with longer extremities usually have slower distal nerves,22 probably associated with a distal tapering of the nerve. Finally, if distal nerve waveforms are unobtainable, one should test more proximal nerves (ie, axillary or femoral nerve). Most neuropathies affect the distal nerves more than the proximal nerves, because the distal nerves are longer. The electromyographer must ascertain that the problem is not more widespread. A normal proximal nerve segment may help clarify a distal PN. Like any good puzzle, all the pieces have to fit together. Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
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Educational Activity: To discuss the application of electrodiagnostic medicine in evaluating a difficult-towean, ventilator-dependent patient in the intensive care unit.
The reasons for difficulty weaning a ventilator-dependent patient may be related to the initial pathology or to subsequent events. Electrodiagnostic testing can help determine the reason for the respiratory dysfunction and therefore suggest treatment options, provide clinical information on which to prognosticate, or provide guidance about further ventilatory support. Many patients in intensive care units (ICUs) require intubation because of a primary lung disease or an airway obstruction. Others require ventilatory support because of nervous system dysfunction. This dysfunction may be central (encephalopathy), or peripheral (affecting the anterior horn cells, the peripheral nerves, the myoneural junctions, or the muscles themselves). The peripheral nervous system (PNS) is easily assessed using electrodiagnostic testing. CNS dysfunction or intrinsic lung pathology may complicate the picture and must be evaluated separately. Several conditions can coexist. Injury to the phrenic nerve can be assessed by phrenic NCS and needle electromyography of the diaphragm. Phrenic nerve stimulation can be accomplished as easily as stimulation of any other peripheral nerve; however, practitioners are often reticent to perform this test because of inexperience. The phrenic nerve is stimulated at the posterior border of the sternocleidomastoid muscle, with the pickup over the xiphoid, the reference over the chest wall (7th intercostal space), and the ground between the active and stimulation sites.23 Needle electromyography of the diaphragm has a low (⬃0.2%) incidence of complications, the most severe being pneumothorax.24 Motor unit action potentials (MUAPs) in the diaphragm are typically of shorter duration and smaller amplitude than peripheral MUAPs. Abnormal spontaneous activity or decreased CMAP amplitudes indicate an axonal lesion to the phrenic nerve or injury to the diaphragm itself. Cervical (C3-5) nerve root disorders can also affect the diaphragm. In these cases, needle electromyography of the upper cervical paraspinal muscles should demonstrate abnormalities. Needle electromyography of higher intercostal muscles, pectoralis muscles, or other muscles may yield more data. Trauma to, or compression of, the phrenic nerve may occur because of neoplasm, direct trauma, or from surgery. Retractors, instruments, or inadvertent clamping may cause injury to the phrenic nerve. The phrenic nerve may also be damaged during open-heart surgery if myocardial hypothermia is utilized: 10% to 44% of postcoronary artery bypass graft patients have elevation of the hemidiaphragm postoperatively.25 The respiratory neuromuscular system may also be affected by PN, motoneuron disease, myopathy, or neuromuscular junction disorders. While PN usually affects primarily distal muscles, several neuropathies, including acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and porphyric polyneuropathy, can affect the proximal respiratory muscles. Specifically, AIDP can affect respiration in up to 30% of patients. In addition to causing phrenic neuropathy, the dysautonomic state that is seen increases the risk of intubation by exaggerating the hypotensive response to sedative agents and increasing the risk of arrhythmias.26 In AIDP, the phrenic nerve conduction latencies may be prolonged. With axonal damage, abnormal spontaneous activity of the diaphragm may be noted with needle electromyography, and the CMAP amplitude may be diminished. Patients with porphyric neuropathy demonstrate a primarily axonal neuropathy. In such cases, the electromyogram would yield relatively normal phrenic nerve latencies and Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
NCVs with decreased CMAP amplitudes and abnormal spontaneous activity on needle testing of the diaphragm. Critical illness polyneuropathy (CIP), a specific type of PN, was reported as responsible for 13% to 76% of chronically critically ill patients who required prolonged ventilatory support.25 Suggested mechanisms for CIP include a systemic inflammatory response, sepsis, hyperglycemia, and insulin deficiency.24-27 Pathologic and electrophysiologic studies indicate a primary axonal degeneration of peripheral motor and sensory fibers, without inflammation. Electrodiagnostic testing on patients with CIP reflects primarily axonal involvement. Testing of sensory and motor nerves will show normal or near normal latencies and conduction velocities. The sensory and motor amplitudes will be either significantly decreased or unobtainable. On needle electromyography, abnormal spontaneous activity will be apparent. MUAPs may be reduced in number and fire at an increased frequency. There may be long-duration polyphasic MUAPs noted as well. Myopathy has been implicated in patients who have been difficult to wean from the respirator. Electrophysiologic testing may help determine the reason. However, it should be noted that in steroid myopathy, needle testing might be normal. Critically ill patients frequently have large dose glucocorticoids prescribed for their primary disease. Side effects of the steroids include muscle weakness and atrophy. Glucocorticoid-induced atrophy primarily affects type II muscle fibers. On electrodiagnostic testing, NCSs will be normal, because the peripheral nerve is unaffected. On needle electromyography, because type I fibers are recruited first, no abnormalities will be detected. Critical care myopathy is an acute weakness syndrome affecting critically ill patients who present with sepsis and multiple organ failure. It is also associated with use of corticosteroid or neuromuscular blocking agents. The mechanism is unknown, but is hypothesized to be related to cytokine release.25 Patients receiving corticosteroids or neuromuscular blocking agents may develop a thick-filament myopathy or an acute necrotizing myopathy. Electrodiagnostic testing in a patient with critical care myopathy would reveal normal latencies and NCV, low CMAP amplitudes, and normal SNAP amplitude. On needle electromyography, abnormal spontaneous activity may be noted. The motor units are typically of low amplitude, short duration, and polyphasic with early recruitment. Disorders of neuromuscular transmission should be considered in critically ill patients who present with weakness and difficulty weaning from a ventilator. In particular, Eaton-Lambert myasthenic syndrome and myasthenia gravis should be considered (see Study Guide, Activities 3.3 and 3.628). The difficult-to-wean, ventilator-dependent ICU patient may be suffering from dysfunction of the respiratory system arising anywhere from the CNS or PNS, the neuromuscular junction, or the respiratory muscles. Electrodiagnostic testing is an important tool in the evaluation of these patients, and can guide the clinician in determining further investigation or treatment. References 1. Vinik AI. Management of neuropathy and foot problems in diabetic patients. Clin Cornerstone 2003;5:38-55. 2. Donofrio PD, Albers JW. AAEM Minimonograph #34: polyneuropathy: classification by nerve conduction studies and electromyography. Muscle Nerve 1990;13:889-903. 3. Weiss LD, Silver JK, Weiss J. Easy EMG: a guide to performing nerve conduction studies and electromyography. Edinburgh: Butterworth-Heinemann; 2004.
PERIPHERAL NEUROPATHY, Weiss
4. Douglas D. Tight glucose control over long term protects against diabetic neuropathy. Diabetes Care 2003;26:2400-4. 5. Kowalski KJ, Agre JC. Neuromuscular rehabilitation and electrodiagnosis. 3. Generalized peripheral neuropathy. Phys Med Rehabil 2000;81(Suppl 1):S22-6. *6. Pascuzzi RM. Peripheral neuropathies in clinical practice. Med Clin North Am 2003;87(3):697-724. 7. Backonja MM. Use of anticonvulsants for treatment of neuropathic pain. Neurology 2002;59(5 Suppl 2):S14-7. 8. McCleane G. 200 mg daily of lamotrigine has no analgesic effect in neuropathic pain: a randomised double-blind, placebo controlled trial. Pain 1999;83:105-7. 9. Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001;57:505-9. 10. Sang CN, Boohjer S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology 2002;96:1053-61. 11. Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003;60:927-34. *12. Wulff EA, Simpson DM. HIV-associated peripheral nervous system complications. NeuroAIDS [serial online]. 1999 Mar; 2(3). Available at: http://aidscience.org/neuroaids/articles/ Neuro2(3).asp. Accessed July 15, 2004. *13. Tagliati M, Grinnell J, Godbold J, Simpson DM. Peripheral nerve function in HIV infection: clinical, electrophysiologic, and laboratory findings. Arch Neurol 1999;56:84-9. 14. Bosch EP, Smith BE. Disorders of peripheral nerves. In: Bradley WG, editor. Neurology in clinical practice. 3rd ed. Boston: Butterworth-Heinemann; 2000. p 2121-3. 15. Jay CA. Neurological manifestations of human immunodeficiency virus infection. In: Bradley WG, editor. Neurology in clinical practice. 3rd ed. Boston: Butterworth-Heinemann; 2000. p 1419-21.
*Key references.
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16. Dumitru D. Generalized peripheral neuropathies. In: Dumitru D, editor. Electrodiagnostic medicine. Philadelphia: Hanley & Belfus; 1995. p 741-850. 17. Schifitto G, McDermott MP, McArthur JC, et al. Incidence of risk factors for HIV-associated distal sensory polyneuropathy. Neurology 2002;58:1764-8. 18. Tan SV, Guiloff RJ. Hypothesis on the pathogenesis of vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS. J Neurol Neurosurg Psychiatry 1998;65:23-8. *19. Gitter AJ, Stolov WC. AAEM Minimonograph #16: instrumentation and measurement in electrodiagnostic medicine. Rochester: American Association of Electrodiagnostic Medicine; 1995. 20. Denys EH. AAEM Minimonograph #14: the influence of temperature in clinical neurophysiology. Rochester: American Association of Electrodiagnostic Medicine; 1991. 21. Dumitru D. Electrodiagnostic medicine I: basic aspects. In: Braddom RL, Buschbacher RM, editors. Physical medicine & rehabilitation. Philadelphia: WB Saunders; 1996. p 104-31. 22. Dumitru D, Zwarts MJ. Electrodiagnostic medicine pitfalls. In: Dumitru D, Amato AA, Zwarts MJ, editors. Electrodiagnostic medicine. 2nd ed. Philadelphia: Hanley & Belfus; 2002. p 54177. 23. DeLisa JA, Lee HJ, Baran EM, Lai KS, Spielholz N. Manual of nerve conduction velocity and clinical neurophysiology. 3rd ed. New York: Raven Pr; 1994. 24. Bolton CF. AAEM Minimonograph #40: clinical neurophysiology of the respiratory system. Rochester: American Association of Electrodiagnostic Medicine; 1993. *25. Lorin S, Nierman DM. Critical illness neuromuscular abnormalities. Crit Care Clin 2002;18:553-68. 26. Marinelli WA, Leatherman JW. Neuromuscular disorders in the intensive care unit. Crit Care Clin 2002;18:915-29. 27. Silwa JA. Acute weakness syndromes in the critically ill patient. Arch Phys Med Rehabil 2000;81(Suppl 1):S45-52. 28. Strommen JA, Johns JS, Kim CT, et al. Neuromuscular rehabilitation and electrodiagnosis. 3. Diseases of muscles and neuromuscular junction. Arch Phys Med Rehabil 2005;86(3 Suppl 1):S18-27.
Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
Neuromuscular Rehabilitation and Electrodiagnosis. 2. Peripheral Neuropathy Lyn D. Weiss, MD, Jay M. Weiss, MD, Jeffery S. Johns, MD, Jeffrey A. Strommen, MD, Chong-Tae Kim, MD, PhD, Faren H. Williams, MD, MS, Ira G. Rashbaum, MD ABSTRACT. Weiss LD, Weiss JM, Johns JS, Strommen JA, Kim C-T, Williams FH, Rashbaum IG. Neuromuscular rehabilitation and electrodiagnosis. 2. Peripheral neuropathy. Arch Phys Med Rehabil 2005;86(3 Suppl 1):S11-7. This self-directed learning module highlights peripheral neuropathies. It is part of the chapter on neuromuscular rehabilitation and electrodiagnosis in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on diagnostic criteria and classifications of peripheral neuropathy, including diabetic, alcoholic, carcinomatous, human immunodeficiency virus–associated, and critical illness polyneuropathies. Treatment options are reviewed. The causes for difficult to obtain nerve conduction studies are highlighted. Overall Article Objective: To summarize the diagnosis, classification, and treatment of peripheral neuropathies. Key Words: Alcoholic neuropathy; Carcinoma; Critical illness; Electrodiagnosis; HIV; Peripheral neuropathies; Rehabilitation; Treatment outcome. © 2005 by the American Academy of Physical Medicine and Rehabilitation 2.1
Clinical Activity: To clarify electrodiagnostic medicine’s role in establishing the cause of bilateral hand and foot numbness with pain in a 64-year-old woman with diabetes, breast cancer, and alcoholism.
The electromyographer has a responsibility to provide the referring physician with as much physiologic information as possible about both diagnosis and prognosis. In a case of possible peripheral neuropathy (PN), the history must include elements of duration, location, and intensity of symptoms, information about any relatives with similar disorders to assess for a hereditary neuropathy, previous cancers and their treatments, if any, and other medical problems that can be associated with PN. These include diabetes, hypothyroidism, human immunodeficiency virus (HIV), side effects from medications, alcoholism, uremia, toxic exposures, connective tissue disorders, infectious processes, and nutritional deficiencies. The
From the Department of Physical Medicine and Rehabilitation, Nassau University Medical Center, East Meadow, NY (LD Weiss); Long Island PMR, Levittown, NY (JM Weiss); Department of Physical Medicine and Rehabilitation, Charlotte Institute of Rehabilitation, Charlotte, NC (Johns); Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN (Strommen); Division of Child Development and Rehabilitation, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA (Kim); Section of Physical Medicine and Rehabilitation, Philadelphia Veterans Administration Medical Center and University of Pennsylvania, Philadelphia, PA (Williams); and Department of Rehabilitation Medicine, New York University Medical Center, New York, NY (Rashbaum). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Lyn D. Weiss, MD, Nassau University Med Ctr, Dept of PM&R, 2201 Hempstead Tpke, East Meadow, NY 11554, e-mail: [email protected]. 0003-9993/05/8603S-9586$30.00/0 doi:10.1016/j.apmr.2004.12.004
physical examination may help differentiate a PN (generally distal) from a localized peripheral nerve entrapment. The diagnosis of PN typically requires an electrodiagnostic examination of at least 3 limbs, including both sensory and motor studies, as well as needle testing. The temperature of the limbs should be maintained at 32°C in the upper extremities and 30°C in the lower extremities. Decreased temperatures can lead to spuriously false results on nerve conduction studies (NCSs), including increased amplitudes, prolonged latencies, and slowed nerve conduction velocities (NCVs). Once the diagnosis of PN is clear, the electromyographer should clarify its type in order to determine the cause and severity. PN can be grouped into primarily axonal, primarily demyelinating, or mixed. It can further be divided into those neuropathies that affect primarily motor fibers, sensory fibers, or both. It can be classified as segmental (affecting only certain areas of the nerve) or uniform (affecting the entire length of the nerve). The referring physician will also need to know the severity of the PN. Furthermore, a thorough electrodiagnostic study may reveal a superimposed peripheral nerve entrapment, because patients with PN are frequently predisposed to compression neuropathies. Needle electromyography is an important component of the evaluation. In axonal neuropathies, the chronicity of the lesion can be estimated based on needle findings. Large amplitude, long duration, polyphasic motor units are consistent with a more chronic (⬎6-mo) process. Needle studies are also indicated to determine if other conditions are superimposed on the neuropathy. For example, needle abnormalities limited to a peripheral nerve distribution may point to a superimposed mononeuropathy. Needle abnormalities only in the paraspinal muscles may suggest a polyradiculopathy. In this patient, several types of neuropathy are suggested by the presentation. The history of diabetes would suggest diabetic neuropathy (DN). DN represents a spectrum of different syndromes, ranging from subclinical to clinical, depending on the nerve fibers involved.1 DN will affect both motor and sensory fibers, and have both demyelinating and axonal components. This will frequently present with numbness in a stocking and glove distribution and with distal muscle wasting. Alcoholic neuropathy, primarily an axonal sensory and motor neuropathy, has an unclear etiology. It is most likely caused either by a direct toxic effect of the alcohol or by a nutritional deficiency of the vitamin B group, giving symptoms in a stocking and glove distribution. Carcinomatous neuropathy, an axonal sensory neuropathy with a stocking and glove presentation, is characterized by decreased amplitude of the sensory nerve action potential (SNAP) with generally normal or near normal latencies and unaffected motor studies. Because there is usually sparing of the motor axons, the needle electromyography will usually appear normal. Neuropathy associated with chemotherapeutic agents has a variable presentation depending on the type of agent. Cisplatin toxicity typically presents with a sensory axonal neuropathy. Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
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Vincristine neuropathy typically presents with an axonal neuropathy that involves motor nerves more than sensory nerves.2 Other possible causes of PN in this patient include trauma associated with surgery (especially positioning), nerve damage during axillary node dissection, radiation plexopathy, or a paraneoplastic syndrome. Radiation plexopathy and trauma associated with surgery would not give a bilateral stocking and glove distribution, as was presented here, but can be a complicating factor in the diagnosis. Radiation plexopathy will classically show myokymic discharges (a sound described as marching soldiers) on needle electromyography. Paraneoplastic syndrome neuropathy typically demonstrates axonal loss, affecting motor more than sensory nerves. While the nerve study and needle electromyography are both important, in PN the NCSs take on greater importance. NCSs can distinguish between demyelinating and axonal lesions, and sensory fibers are not assessed by needle electromyography. The most important part of the electrodiagnostic consult is to place the data into the appropriate clinical context. The findings should note the primary electrophysiologic lesion. For example, if the patient has generally mildly increased distal latencies and mild slowing, but SNAP amplitudes in the arms and legs are unobtainable or severely decreased, then the primary lesion is an axonal sensory neuropathy. Theoretically, the latency and NCV should not be affected in an axonal neuropathy. However, because some of the fastest fibers may be affected in an axonal lesion, a mild reduction in NCV may be noted. An NCV reduction of 70% to 80% or more, compared to the contralateral side or the distal segment, would be considered significant. There may be a concomitant demyelinating motor neuropathy that complicates the picture. These findings must be discussed in the clinical context. Table 1 delineates the possible causes of neuropathy as revealed by the electrodiagnostic findings.3 2.2
Clinical Activity: To delineate treatment options in this patient.
Once PN has been diagnosed, treatment options should be initiated. Although a plethora of treatments exists, none is a panacea. Usually, trials of different medications titrated to effective dosage must be attempted before the most adequate treatment is instituted. The first objective is to treat or remove the underlying cause for the PN. Electrodiagnosis can help categorize the neuropathy type (ie, axonal or demyelinating, sensory or motor, uniform or segmental). Often, other tests are required to confirm the diagnosis. If axonal neuropathy was evident, and the patient had an extensive history of alcohol use, blood samples should be obtained to assess for nutritional deficiencies. Cessation of alcohol, vitamin supplementation (specifically B vitamins and magnesium), and dietary changes may decrease the symptoms of neuropathy. The most important preventive measure for type 1 DN appears to be adequate glucose control.4 Medications for PN generally fall into the following categories: tricyclic agents, anticonvulsants, antiarrhythmics, topical solutions, clonidine, and opioids.5 Nonpharmaceutical treatments should be considered as adjuvants to medication, especially in patients who are unable to tolerate the full dosage because of contraindications or side effects. These include transcutaneous electric nerve stimulation, heat, ice, biofeedback, meditation, acupuncture, and hypnosis. Titrated doses of several medications may be tried before an adequate response is obtained. First-line choices often depend on the characteristics of neuropathic pain.6 Anticonvulsants are usually the first medication prescribed for trigeminal neuralgia. Continuous burning dysesthesias, such as those seen in DN, Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
usually respond to tricyclic agents. Therapy should be oriented toward the treatment of pain, based on the proposed mechanism for pain generation. The tricyclic agents are a good first-line medication for patients with neuropathy. They have the added benefit of a positive effect on mood, although patients are typically started on a dose that would be considered subtherapeutic to treat depression. The mechanism of action is not known. Amitriptyline, nortriptyline, imipramine, and desipramine have been successfully used. Typical starting dose for amitriptyline is 25mg at bedtime. The dose must be gradually titrated for maximum effect before switching to another medication. The dosage can be increased by 10 to 25mg every 3 to 7 days up to a total of 150mg. Usually 3 to 4 weeks of medication is required before an effect is noted. Anticonvulsants have also been used with success in treating neuropathies. Phenytoin, carbamazepine, and gabapentin have been most frequently used. Gabapentin has gained increasing popularity because of its low side-effect profile. Patients can be started at 300mg at night, and quickly titrated to up to 1200mg (or occasionally greater) 3 times a day. Gabapentin may be effective in neuropathic pain because of its effect on calcium channels. The rationale for using anticonvulsants is based on the similarities between the pathophysiologic and biochemical mechanisms in both epilepsy and neuropathy. Apparently, primary afferent fibers are susceptible to the effects of sodium and calcium channel blockade. Blocking these channels would theoretically reduce spontaneous and evoked neural discharges.7 The efficacy of some of the newer anticonvulsant medications, including lamotrigine and zonisamide, is still being evaluated.7-9 Antiarrhythmics such as intravenous lidocaine and oral mexiletine, which block sodium channels, have been used in neuropathic disorders. These medications are not as frequently prescribed because of their high side-effect profile. Intravenous lidocaine must be administered in a recovery room or other monitored setting because of the risk of seizures or cardiac arrhythmias. Any patient with a cardiac history or abnormal electrocardiogram should have cardiology clearance before starting mexiletine. Recently, the use of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists has been used to treat patients with painful DN. The mechanism of action is antagonism of voltage-dependent calcium channels and NMDA receptor operated channels. Whereas dextromethorphan was noted to be effective in a dose-related fashion in selected DN patients, it was not effective in postherpetic neuralgia, suggesting a difference in the pain mechanism.10 Topical preparations, such as lidocaine, capsaicin cream, or clonidine, have the advantage of decreased systemic effects. Capsaicin is thought to decrease pain by depleting substance P.5 However, it produces intense burning and must be applied 3 to 4 times per day. The efficacy of these topical agents has been questioned.5 Use of opioids in neuropathic pain remains controversial. They may be more efficacious if used in combination with other agents. The starting dosage should be low and titrated to maximum effectiveness. Recent studies11 with controlled-release oxycodone showed it to be effective in the treatment of painful DN. Choosing the most appropriate medication and dosage requires patience on the part of both the clinician and the patient. The goal of therapy is to provide optimal analgesia with a minimum of side effects.
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PERIPHERAL NEUROPATHY, Weiss Table 1: Classification and Electrodiagnostic Findings of PN
EMG Finding CMAP amplitude Motor latency Motor conduction velocity Dispersion of CMAP SNAP amplitude SNAP conduction velocity Needle EMG: Would fibs and PSWs likely be noted? Common diseases
Uniform Demyelinating Mixed Sensorimotor PN Normal
Segmental Demyelinating Motor ⬎ Sensory PN
Axon Loss Motor ⬎ Sensory PN
Sensory Axon Loss Neuropathy
Axon Loss Mixed Sensorimotor PN
Mixed Axonal Loss and Demyelinating Sensorimotor PN
Decreased
Normal
Decreased
Decreased
Increased Decreased
Decreased secondary to dispersion Increased Decreased
Normal Normal
Normal Normal
Normal Normal
Increased Decreased
No
Yes
No
No
No
Yes (mild)
Normal
Normal
Decreased (usually)
Decreased
Decreased
Decreased
Decreased
Decreased (somewhat)
Normal
Normal
Normal
Decreased
No (normal)
No (normal)
Yes
No (normal)
Yes
Yes
1. Hereditary motor sensory neuropathy type 1, 3, 6 (distal weakness with little atrophy) 2. Metachromatic leukodystrophy 3. Krabbe’s leukodystrophy 4. Adrenomyeloneuropathy 5. Congenital hypomyelinating neuropathy 6. Tangier disease 7. Cockayne’s syndrome 8. Cerebrotendinous xanthomatosis
1. AIDP: GuillainBarré syndrome (ascending proximal weakness) 2. CIDP (weakness of asymmetric low extremities) 3. Recurrent inflammatory PN (proximal weakness) 4. Osteosclerotic myeloma 5. Hypothyroidism (sensory ⬎ motor) (distal symmetric weakness) 6. Leprosy 7. Acute arsenic PN 8. Pharmaceuticals: amiodarone, perhexiline, high-dose Ara-C 9. Carcinoma 10. AIDS
1. Remote-effect motor neuropathy associated with carcinoma (distal weakness) 2. Porphyria 3. Axonal GuillainBarré syndrome 4. Hereditary motor sensory neuropathy types 2 and 5 5. Lead neuropathy 6. Dapsone neuropathy 7. Vincristine neuropathy 8. Remote-effect motor neuropathy associated with lymphoma 9. Hypoglycemia hyperinsulinemia
1. Carcinomatous (neuropathic pain in distal extremities) 2. Hereditary sensory neuropathy types 1– 4 3. Friedreich’s ataxia 4. Spinocerebellar degeneration 5. Abetalipoproteinema (Bassen-Kornzweig disease) 6. Primary biliary cirrhosis 7. Acute sensory neuronopathy cisplatin toxicity 8. Lymphomatous sensory neuronopathy 9. Chronic idiopathic ataxic neuropathy 10. Sjögren’s syndrome 11. Fisher-variant Guillain-Barré syndrome 12. Paraproteinemias 13. Pyridoxine toxicity
1. Alcoholic PN (distal symmetric weakness) 2. Vitamin (thiamine, B12, folate) deficiency (distal symmetric weakness) 3. Gouty neuropathy 4. Metal neuropathy (eg, mercury, thallium, gold) 5. Sarcoidosis 6. Connective tissue diseases (eg, rheumatoid arthritis, SLE) 7. Gastrectomy, gastric restriction surgery for obesity 8. Chronic liver disease 9. Neuropathy of chronic illness (eg, hypothyroidism, myotonic dystrophy, AIDS, Lyme disease) 10. Toxic neuropathy (acrylamide, carbon disulfide, carbon monoxide)
1. Diabetic PN (distal symmetric weakness) 2. Uremia (distal symmetric weakness)
Reprinted with permission from Weiss et al.3 Abbreviations: AIDP, acute inflammatory demyelinating polyradiculoneuropathy; AIDS, acquired immunodeficiency syndrome; CIDP, chronic inflammatory demyelinating polyneuropathy; CMAP, compound motor action potential; EMG, electromyography; fibs, fibrillation potentials; PSWs, positive sharp waves; SLE, systemic lupus erythematosus.
2.3
Clinical Activity: To comment on the investigation and care of a 57-year-old man who is seropositive for HIV and presenting with distal weakness and sensory disturbances.
Neuromuscular disorders, including primary myopathies and PNs, are the most frequent neurologic complications of HIV and acquired immune deficiency syndrome (AIDS).12 The estimated prevalence of some form of PN in patients with HIV is 15% to 45%, based on clinical findings, but may be higher if electrophysiologic or nerve biopsy findings are considered.13,14
Although this patient has symptoms consistent with a PN, myopathies must be considered. HIV-associated myopathies occur in 3 primary forms: inflammatory myopathy, zidovudine myopathy, and pyomyositis.15 The inflammatory form can occur at any point in the course of HIV infection and results in proximal weakness and, less commonly, myalgias. Creatine kinase (CK) may be elevated, and electromyography findings include myopathic motor units and abnormal spontaneous activity typical of an inflammatory myopathy. Muscle biopsy findings include fiber size variability, fiber degeneration, and endomysial infiltrates along Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
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with cytoplasmic bodies and nemaline rod bodies.15 The exact pathogenesis of this inflammatory myopathy is not known, but HIV does not appear to infect muscle fibers directly, and triggers cell-mediated muscle injury by expressing major histocompatibility complex 1.12 Treatment is reserved only for significant weakness that impairs function and includes cautious use of corticosteroids. Zidovudine myopathy is clinically difficult to distinguish from the inflammatory form. It presents with an insidious onset of proximal weakness and myalgia with a normal or elevated CK. Patients typically have taken zidovudine for at least 6 months, and muscle biopsy suggests mitochondrial dysfunction, with varying degrees of inflammation.15 Pyomyositis is a focal, suppurative bacterial muscle infection presenting with fever, local muscle pain, and swelling evolving over several weeks. White blood cell count and CK are usually normal, and the diagnosis can be made using computed tomography, magnetic resonance imaging (MRI), or ultrasound. The causative organism is typically Staphylococcus aureus, or, less commonly, Salmonella or other gram-negative bacilli. Treatment includes antibiotics and possible surgical drainage.15 HIV-associated peripheral nerve disorders have been classified into at least 5 main categories: distal symmetric polyneuropathy, inflammatory demyelinating polyneuropathy, mononeuropathy multiplex, progressive polyradiculopathy, and autonomic neuropathy.12,16 Others include diffuse infiltrative lymphocytosis syndrome and herpes zoster radiculitis.12,14 Distal symmetric PN is the most common form of peripheral nerve disorder in patients with HIV.13,16 It affects 25% to 38% of patients with HIV and up to 48% to 52% of patients with AIDS.12,13,17 There is a correlation with lower hemoglobin, lower functional status, and, possibly, advanced age.12,13,17 Symptoms include ascending distal numbness, paresthesias, and painful dysesthesias usually beginning in the toes.12,13,16 Clinical signs include reduced sensation to vibration, pain, and temperature in a stocking distribution, mildly reduced foot intrinsic strength with mild wasting, and absent or depressed ankle reflexes.12,13,16 Hyperactive knee reflexes may indicate central nervous system (CNS) dysfunction, such as myelopathy.12 Position sense loss associated with distal symmetric PN has a reported occurrence of 19%.13 Advanced cases may also involve the upper extremities in a distal and symmetrical pattern.12 Hand intrinsic strength is typically preserved until late in the disease course.16 Nerve biopsies reveal predominately axonal loss with Wallerian-like degeneration of myelinated and unmyelinated fibers.18 Possible causes include cytomegalovirus (CMV), inflammatory processes, nutritional deficiencies, and diabetes; however, most patients have no identifiable cause.18 A subset of patients with distal symmetric PN may also have necrotizing vasculitis.14 Distal symmetric PN may also be mimicked by toxic neuropathies from medications such as zalcitabine, didanosine, and stavudine.17 Diagnosis of distal symmetric PN is typically clinical, and alternative causes of neuropathy should be ruled out. Electrodiagnostic findings are consistent with a distal axonal sensory and motor polyneuropathy and include reduced sensory and motor nerve amplitudes and, to a lesser extent, the NCV, prolonged late responses, and neurogenic changes in the distal leg muscles on needle electromyography.12,16 Treatment of distal symmetric PN is primarily symptomatic, but investigational trials are ongoing using recombinant human nerve growth factor and prouridine.12 The incidence of HIV-related inflammatory demyelinating PN is approximately 4%,13 and occurs in an acute or a chronic form. The acute form often occurs at the time of seroconversion to HIV positivity.12 Clinical features, electrodiagnostic Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
findings, and pathogenesis of the acute form are similar for people with or without HIV infection. CMV may cause inflammatory demyelinating PN by directly infecting peripheral nerves, but nerve biopsies typically demonstrate primarily segmental demyelination with variable degrees of axonal loss.12,16 Cerebrospinal fluid (CSF) shows elevated protein and lymphocytic pleocytosis, which differs from the acellular CSF of typical acute inflammatory demyelinating PN.12,14 Given the similarities in clinical presentation and diagnostic findings, consider HIV testing in any patient with acute or chronic inflammatory demyelinating PN with HIV risk factors or suspicious laboratory results.14 Treatment includes corticosteroids, plasmapheresis, and high-dose intravenous immunoglobulin.12,15 HIV-related mononeuropathy multiplex occurs in 2 forms, one occurring in immunocompetent patients and probably immune mediated, self-limiting, and showing a good response to corticosteroids, and the other being more progressive and extensive and occurring in immunocompromised patients (CD4 ⬍50).12,14,15 One study13 found the overall incidence of mononeuropathy multiplex to be 11% in HIV-positive patients. Clinical presentation includes reduced sensation or paresthesias in a pattern suggesting multiple peripheral nerves or cutaneous sensory nerves rather than a nerve root or symmetric disorder of all distal nerves. Marked asymmetry is typical, and strength and reflexes are normal in nonaffected peripheral nerve distributions.16 There are 3 primary histopathologies: most commonly, a combination of perivascular inflammation and axonal loss; occasionally, a combination of demyelination and axonal loss with multinucleated inflammatory cells; and, least commonly, a vasculitic lesion that creates a pattern of necrotizing vasculitis.16 Electromyography findings of mononeuropathy multiplex include multifocal and asymmetric pathology of cranial, sensory, and motor nerves with axonal or demyelinating pathology.12 Mononeuropathy multiplex commonly occurs concurrently with distal symmetric PN.16 Sural nerve biopsy may reveal evidence of primary CMV infection, and CSF studies should include a CMV assay.12 Treatment considerations for CMV infection may include ganciclovir, foscarnet, and cidofovir alone or in combination.12 The incidence of patients with HIV-related progressive polyradiculopathy is approximately 1%,13 and it occurs mainly in late stages of the disease.12,16 It is typically associated with opportunistic infections, typically CMV, and more rarely, syphilis, mycobacterial infections, toxoplasmosis, and leptomeningeal lymphomatosis.14,15 Clinical presentation includes radiating pain and paresthesias in the cauda equina distribution, rapidly progressive flaccid paraparesis, lower-extremity areflexia, mild sensory loss including the perineum, and neurogenic bowel and bladder.12,14-16 In a patient with a thoracic or cervical sensory level lesion, a concurrent myelopathy should be considered. Nerve root biopsies typically reveal CMV inclusions as well as significant degrees of inflammatory infiltrates associated with varying degrees of axonal loss.16 Electromyography findings are variable and include low-amplitude compound muscle action potentials (CMAPs), prolonged or absent F waves, reduced or absent SNAPs, and diffuse abnormal spontaneous activity on needle electromyography.16 CSF reveals marked polymorphonuclear pleocytosis, elevated protein, and low to normal glucose with cultures or assays positive for CMV.12,15 MRI with gadolinium may demonstrate enhancement of cauda equina nerve roots.14 Treatment is targeted toward CMV as discussed for mononeuropathy multiplex above.12 This CMV treatment may preserve neurologic function; however, the patient’s long-term prognosis is poor.14
PERIPHERAL NEUROPATHY, Weiss
The incidence of HIV-related autonomic neuropathy is approximately 1%.13 Findings may include resting tachycardia, orthostatic hypotension, syncope, impotence, urinary dysfunction, diarrhea, and anhidrosis. The exact pathophysiology is unknown but is thought to be caused by multiple factors. The diagnosis is clinical, and treatment is supportive and symptombased.12 Herpes zoster radiculitis occurs in about 10% of patients with HIV and may present early in the disease, at the time of seroconversion, or during asymptomatic periods. Ataxia from polyganglionopathy may develop.14 Symptoms and treatment are similar to HIV-seronegative patients. 2.4
Clinical Activity: To list the potential causes of difficulty obtaining NCSs in this patient.
There may be several technical reasons for obtaining an abnormal waveform, assuming that there are no physiologic reasons. One of the most common reasons is inappropriate gain and/or sweep setting. Patients with PN may have prolonged latencies, low amplitudes, and slowed NCVs. If the gain is set too low, the waveform amplitude and takeoff may not be readily observed. Increasing the gain will help identify the waveform and its parameters.19 If the sweep speed is too slow, the takeoff may be to the right of the screen. Increasing the sweep speed will help identify waveforms that have very prolonged latencies. In instances of unobtainable CMAPs or SNAPs, the initial assumption should be that this is caused by technical factors, including failure to stimulate the nerve or a failure to record the evoked response properly. If nerve stimulation elicits a visible contraction in the appropriate muscle, the stimulator is functioning and the nerve is being depolarized, so one should increase the intensity and/or the pulse width. If a shock is not felt, the problem may be a lack of stimulus. Check wires and settings or replace the stimulator. If the stimulator is functioning, check proper positioning and/or stimulate a more superficial or consistent site. For example, a CMAP that is obtainable proximally and not distally suggests poor localization of the stimulator or perhaps an anomalous innervation, not a neuropathic process. If there is a problem with the waveform recording, check that the preamplifier is not turned off. Check the wires, and lightly touch one of the electrodes. If the speaker is on, you should hear noise from the electrode (especially with a sensory test set-up). If there is no noise, there probably is a technical problem. Recheck settings, including which amplifier/preamplifier (if more than 1 channel) is on. A study should be considered unobtainable only after methodically ruling out a problem stimulating a nerve or a problem with recording. At this point, a different nerve should be stimulated to check for recording. For example, in motor nerves, if a CMAP is unobtainable from the median nerve at the abductor pollicis brevis muscle, stimulate the ulnar nerve with the same pickup. The ulnar innervated thenar muscles will give a CMAP verifying that the stimulator, electrodes, and preamplifier and circuitry are working. Similarly, sensory studies can be performed on digits with dual innervation (digit 1 for radial and median nerves, digit 4 for median and ulnar nerves). Another common problem, especially in PN patients, is distal muscle wasting. If the active electrode is over an atrophied muscle, the CMAP amplitude will be low, giving the false impression that there is axonal injury. One should test a more proximal muscle innervated by the same nerve.
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For example, if the extensor digitorum brevis (EDB) is atrophied, move the active electrode to the tibialis anterior. If a normal CMAP is obtained, the problem may be an axonal injury to the peroneal nerve distal to the branch to the tibialis anterior muscle, or it may be caused by an atrophied EDB muscle, either from a PN or from non-neuropathic factors such as tight shoes. Temperature can also change the latency, NCV, and amplitude of waveforms. PN patients frequently have concurrent vascular disorders, occasionally associated with cold extremities. Warming the extremity to 30°C in the lower limbs and to 32°C in the upper limbs could decrease the amplitude and distal latency, but increase the NCV. In general, latency is prolonged 0.2ms per degree Celsius, and conduction velocity decreases 1.8 to 2.4m/s per degree Celsius.20 Any outside electric interference can distort or obliterate a waveform. Checking all wires, ensuring the ground is in place (and located between the recording and stimulating electrodes), ensuring all contacts are complete, and trying to decrease outside interference (eg, lights, radios) can help. Because most electric interference is 60 cycles, many electromyographs have a 60-cycle notch filter that selectively filters out all 60-cycle waves. Sometimes, using a shorter wire, especially with SNAPs, can decrease interference. Ensuring that filter settings and impedance are appropriate is essential. Cleansing the skin with alcohol or an abrading agent may help to decrease impedance. Another common source of error is not stimulating directly over the nerve. If this occurs, the amplitude will appear spuriously lower. Furthermore, if there is appreciable adipose tissue, connective tissue, or fluid between the nerve and the stimulator, the amplitude will appear decreased because of submaximal stimulation. Sometimes, increasing the stimulation or the pulse width may help this situation. However, if the stimulation and/or pulse width are too high, a nearby nerve may be mistakenly stimulated, leading to volume conduction. Excessive stimulation can cause depolarization further away from the cathode, the equivalent of stimulating further down the nerve, and giving a falsely increased NCV. With excessive adipose tissue, needle testing can be misleading. If the active electrode is not over the motor point of the nerve, the amplitude may appear decreased, and the CMAP may have an initial positive deflection. Initial positive deflections can also be seen in cases of anomalous innervation, the most commonly being the Martin-Gruber anastomosis and the accessory peroneal nerve. Age, weight, and height can also affect the expected waveform morphology. NCSs are often performed on older patients to assess for PN. NCVs can decrease by 1 to 2m/s per decade of life.21 Amplitudes also can be expected to decrease with increasing age. Patients with longer extremities usually have slower distal nerves,22 probably associated with a distal tapering of the nerve. Finally, if distal nerve waveforms are unobtainable, one should test more proximal nerves (ie, axillary or femoral nerve). Most neuropathies affect the distal nerves more than the proximal nerves, because the distal nerves are longer. The electromyographer must ascertain that the problem is not more widespread. A normal proximal nerve segment may help clarify a distal PN. Like any good puzzle, all the pieces have to fit together. Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
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Educational Activity: To discuss the application of electrodiagnostic medicine in evaluating a difficult-towean, ventilator-dependent patient in the intensive care unit.
The reasons for difficulty weaning a ventilator-dependent patient may be related to the initial pathology or to subsequent events. Electrodiagnostic testing can help determine the reason for the respiratory dysfunction and therefore suggest treatment options, provide clinical information on which to prognosticate, or provide guidance about further ventilatory support. Many patients in intensive care units (ICUs) require intubation because of a primary lung disease or an airway obstruction. Others require ventilatory support because of nervous system dysfunction. This dysfunction may be central (encephalopathy), or peripheral (affecting the anterior horn cells, the peripheral nerves, the myoneural junctions, or the muscles themselves). The peripheral nervous system (PNS) is easily assessed using electrodiagnostic testing. CNS dysfunction or intrinsic lung pathology may complicate the picture and must be evaluated separately. Several conditions can coexist. Injury to the phrenic nerve can be assessed by phrenic NCS and needle electromyography of the diaphragm. Phrenic nerve stimulation can be accomplished as easily as stimulation of any other peripheral nerve; however, practitioners are often reticent to perform this test because of inexperience. The phrenic nerve is stimulated at the posterior border of the sternocleidomastoid muscle, with the pickup over the xiphoid, the reference over the chest wall (7th intercostal space), and the ground between the active and stimulation sites.23 Needle electromyography of the diaphragm has a low (⬃0.2%) incidence of complications, the most severe being pneumothorax.24 Motor unit action potentials (MUAPs) in the diaphragm are typically of shorter duration and smaller amplitude than peripheral MUAPs. Abnormal spontaneous activity or decreased CMAP amplitudes indicate an axonal lesion to the phrenic nerve or injury to the diaphragm itself. Cervical (C3-5) nerve root disorders can also affect the diaphragm. In these cases, needle electromyography of the upper cervical paraspinal muscles should demonstrate abnormalities. Needle electromyography of higher intercostal muscles, pectoralis muscles, or other muscles may yield more data. Trauma to, or compression of, the phrenic nerve may occur because of neoplasm, direct trauma, or from surgery. Retractors, instruments, or inadvertent clamping may cause injury to the phrenic nerve. The phrenic nerve may also be damaged during open-heart surgery if myocardial hypothermia is utilized: 10% to 44% of postcoronary artery bypass graft patients have elevation of the hemidiaphragm postoperatively.25 The respiratory neuromuscular system may also be affected by PN, motoneuron disease, myopathy, or neuromuscular junction disorders. While PN usually affects primarily distal muscles, several neuropathies, including acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and porphyric polyneuropathy, can affect the proximal respiratory muscles. Specifically, AIDP can affect respiration in up to 30% of patients. In addition to causing phrenic neuropathy, the dysautonomic state that is seen increases the risk of intubation by exaggerating the hypotensive response to sedative agents and increasing the risk of arrhythmias.26 In AIDP, the phrenic nerve conduction latencies may be prolonged. With axonal damage, abnormal spontaneous activity of the diaphragm may be noted with needle electromyography, and the CMAP amplitude may be diminished. Patients with porphyric neuropathy demonstrate a primarily axonal neuropathy. In such cases, the electromyogram would yield relatively normal phrenic nerve latencies and Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
NCVs with decreased CMAP amplitudes and abnormal spontaneous activity on needle testing of the diaphragm. Critical illness polyneuropathy (CIP), a specific type of PN, was reported as responsible for 13% to 76% of chronically critically ill patients who required prolonged ventilatory support.25 Suggested mechanisms for CIP include a systemic inflammatory response, sepsis, hyperglycemia, and insulin deficiency.24-27 Pathologic and electrophysiologic studies indicate a primary axonal degeneration of peripheral motor and sensory fibers, without inflammation. Electrodiagnostic testing on patients with CIP reflects primarily axonal involvement. Testing of sensory and motor nerves will show normal or near normal latencies and conduction velocities. The sensory and motor amplitudes will be either significantly decreased or unobtainable. On needle electromyography, abnormal spontaneous activity will be apparent. MUAPs may be reduced in number and fire at an increased frequency. There may be long-duration polyphasic MUAPs noted as well. Myopathy has been implicated in patients who have been difficult to wean from the respirator. Electrophysiologic testing may help determine the reason. However, it should be noted that in steroid myopathy, needle testing might be normal. Critically ill patients frequently have large dose glucocorticoids prescribed for their primary disease. Side effects of the steroids include muscle weakness and atrophy. Glucocorticoid-induced atrophy primarily affects type II muscle fibers. On electrodiagnostic testing, NCSs will be normal, because the peripheral nerve is unaffected. On needle electromyography, because type I fibers are recruited first, no abnormalities will be detected. Critical care myopathy is an acute weakness syndrome affecting critically ill patients who present with sepsis and multiple organ failure. It is also associated with use of corticosteroid or neuromuscular blocking agents. The mechanism is unknown, but is hypothesized to be related to cytokine release.25 Patients receiving corticosteroids or neuromuscular blocking agents may develop a thick-filament myopathy or an acute necrotizing myopathy. Electrodiagnostic testing in a patient with critical care myopathy would reveal normal latencies and NCV, low CMAP amplitudes, and normal SNAP amplitude. On needle electromyography, abnormal spontaneous activity may be noted. The motor units are typically of low amplitude, short duration, and polyphasic with early recruitment. Disorders of neuromuscular transmission should be considered in critically ill patients who present with weakness and difficulty weaning from a ventilator. In particular, Eaton-Lambert myasthenic syndrome and myasthenia gravis should be considered (see Study Guide, Activities 3.3 and 3.628). The difficult-to-wean, ventilator-dependent ICU patient may be suffering from dysfunction of the respiratory system arising anywhere from the CNS or PNS, the neuromuscular junction, or the respiratory muscles. Electrodiagnostic testing is an important tool in the evaluation of these patients, and can guide the clinician in determining further investigation or treatment. References 1. Vinik AI. Management of neuropathy and foot problems in diabetic patients. Clin Cornerstone 2003;5:38-55. 2. Donofrio PD, Albers JW. AAEM Minimonograph #34: polyneuropathy: classification by nerve conduction studies and electromyography. Muscle Nerve 1990;13:889-903. 3. Weiss LD, Silver JK, Weiss J. Easy EMG: a guide to performing nerve conduction studies and electromyography. Edinburgh: Butterworth-Heinemann; 2004.
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4. Douglas D. Tight glucose control over long term protects against diabetic neuropathy. Diabetes Care 2003;26:2400-4. 5. Kowalski KJ, Agre JC. Neuromuscular rehabilitation and electrodiagnosis. 3. Generalized peripheral neuropathy. Phys Med Rehabil 2000;81(Suppl 1):S22-6. *6. Pascuzzi RM. Peripheral neuropathies in clinical practice. Med Clin North Am 2003;87(3):697-724. 7. Backonja MM. Use of anticonvulsants for treatment of neuropathic pain. Neurology 2002;59(5 Suppl 2):S14-7. 8. McCleane G. 200 mg daily of lamotrigine has no analgesic effect in neuropathic pain: a randomised double-blind, placebo controlled trial. Pain 1999;83:105-7. 9. Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001;57:505-9. 10. Sang CN, Boohjer S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology 2002;96:1053-61. 11. Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003;60:927-34. *12. Wulff EA, Simpson DM. HIV-associated peripheral nervous system complications. NeuroAIDS [serial online]. 1999 Mar; 2(3). Available at: http://aidscience.org/neuroaids/articles/ Neuro2(3).asp. Accessed July 15, 2004. *13. Tagliati M, Grinnell J, Godbold J, Simpson DM. Peripheral nerve function in HIV infection: clinical, electrophysiologic, and laboratory findings. Arch Neurol 1999;56:84-9. 14. Bosch EP, Smith BE. Disorders of peripheral nerves. In: Bradley WG, editor. Neurology in clinical practice. 3rd ed. Boston: Butterworth-Heinemann; 2000. p 2121-3. 15. Jay CA. Neurological manifestations of human immunodeficiency virus infection. In: Bradley WG, editor. Neurology in clinical practice. 3rd ed. Boston: Butterworth-Heinemann; 2000. p 1419-21.
*Key references.
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16. Dumitru D. Generalized peripheral neuropathies. In: Dumitru D, editor. Electrodiagnostic medicine. Philadelphia: Hanley & Belfus; 1995. p 741-850. 17. Schifitto G, McDermott MP, McArthur JC, et al. Incidence of risk factors for HIV-associated distal sensory polyneuropathy. Neurology 2002;58:1764-8. 18. Tan SV, Guiloff RJ. Hypothesis on the pathogenesis of vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS. J Neurol Neurosurg Psychiatry 1998;65:23-8. *19. Gitter AJ, Stolov WC. AAEM Minimonograph #16: instrumentation and measurement in electrodiagnostic medicine. Rochester: American Association of Electrodiagnostic Medicine; 1995. 20. Denys EH. AAEM Minimonograph #14: the influence of temperature in clinical neurophysiology. Rochester: American Association of Electrodiagnostic Medicine; 1991. 21. Dumitru D. Electrodiagnostic medicine I: basic aspects. In: Braddom RL, Buschbacher RM, editors. Physical medicine & rehabilitation. Philadelphia: WB Saunders; 1996. p 104-31. 22. Dumitru D, Zwarts MJ. Electrodiagnostic medicine pitfalls. In: Dumitru D, Amato AA, Zwarts MJ, editors. Electrodiagnostic medicine. 2nd ed. Philadelphia: Hanley & Belfus; 2002. p 54177. 23. DeLisa JA, Lee HJ, Baran EM, Lai KS, Spielholz N. Manual of nerve conduction velocity and clinical neurophysiology. 3rd ed. New York: Raven Pr; 1994. 24. Bolton CF. AAEM Minimonograph #40: clinical neurophysiology of the respiratory system. Rochester: American Association of Electrodiagnostic Medicine; 1993. *25. Lorin S, Nierman DM. Critical illness neuromuscular abnormalities. Crit Care Clin 2002;18:553-68. 26. Marinelli WA, Leatherman JW. Neuromuscular disorders in the intensive care unit. Crit Care Clin 2002;18:915-29. 27. Silwa JA. Acute weakness syndromes in the critically ill patient. Arch Phys Med Rehabil 2000;81(Suppl 1):S45-52. 28. Strommen JA, Johns JS, Kim CT, et al. Neuromuscular rehabilitation and electrodiagnosis. 3. Diseases of muscles and neuromuscular junction. Arch Phys Med Rehabil 2005;86(3 Suppl 1):S18-27.
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